8-39746605-G-C

Variant names:

• chr8-39746605-G-C
• NM_001464.5:c.2041C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001464.5(ADAM2):​c.2041C>G​(p.His681Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.177

Genes affected

ADAM2 (HGNC:198): (ADAM metallopeptidase domain 2) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded protein is a subunit of an integral sperm membrane glycoprotein called fertilin, which plays an important role in sperm-egg interactions. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2462664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5	c.2041C>G	p.His681Asp	missense_variant	Exon 19 of 21	ENST00000265708.9	NP_001455.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM2	ENST00000265708.9	c.2041C>G	p.His681Asp	missense_variant	Exon 19 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.1984C>G	p.His662Asp	missense_variant	Exon 18 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1573C>G	p.His525Asp	missense_variant	Exon 15 of 17	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1852C>G	p.His618Asp	missense_variant	Exon 18 of 20	2		ENSP00000429352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2041C>G (p.H681D) alteration is located in exon 19 (coding exon 19) of the ADAM2 gene. This alteration results from a C to G substitution at nucleotide position 2041, causing the histidine (H) at amino acid position 681 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.0
DANN	Benign	0.36
DEOGEN2	Benign	0.098	.;.;T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.61	T;T;T;T;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	.;.;L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.4	N;N;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.32	T;T;T;.;T
Sift4G	Benign	0.63	T;T;T;T;T
Polyphen		0.0080	B;B;B;B;B
Vest4		0.63
MutPred		0.44		.;.;Gain of ubiquitination at K683 (P = 0.0495);.;.;
MVP		0.81
MPC		0.033
ClinPred		0.082	T
GERP RS		-4.7
Varity_R		0.044
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-39604124;